The long-term goal of this Program is to elucidate how chronic activation of glia (astrocytes and microglia) is linked to neuronal degeneration. We are testing the following hypothesis: Chronic glial activation, with its aberrant regulation of key proteins and signaling pathways, and the consequent dysregulation of normal glialneuronal interactions, promotes neuronal cell death. An increased understanding of glial activation responses will allow new approaches to modulate glial responses that influence neurodegenerative disease progression, while maintaining the important beneficial glial responses necessary for normal brain function. Our focus is on key proteins and pathways that have a documented relationship to end points of Alzheimer's disease (AD) pathology. They have been found to be abnormally regulated in human neurodegenerative disease or in animal models of neurodegenerative disease. W e will determine mechanisms of regulation of the proteins and pathways in activated glia, the relationship between glial protein expression and neuronal function, and the discovery of ligand modulators. Project by Van Eldik will examine the link between selected glial neuroinflammatory responses and neuronal cell death by defining glial cytokine contributions to neuronal death, and using chemical genomics approaches to discover small molecule modulators of neuronal death and death kinases. Project by Binder will focus on the role of abnormal tau in astrocytes and its relationship to their cytoskeletal integrity and ability to undergo the inflammatory response in vitro and in neurodegenerative disease. Project by LaDu will determine how AP induces activation of astrocytes and increases in astrocytic apoE, the role of the apoE receptors LRP and LDLR in these processes, and the extent and mechanism of apoE's anti-inflammatory activity. Project Vassar will test the hypothesis that activated astrocytes surrounding amyloid plaques exacerbate plaque development through BACE1 cleavage of APP to generate Ap during AD inflammation. Two cores have been established to provide services in grant administration and management (Core A: Statistical Core) and to perform histological services (Core B: Histochemistry Core). The projects will utilize a variety of experimental models (cell culture models of primary glia and neurons; novel transgenic and knockout mouse models of AD and related neurodegenerative diseases; and human autopsy tissue) and disciplines (synthetic chemistry, protein biochemistry, cell and molecular biology, physiology and neuropathology). The cooperative and synergistic interactions among investigators with complementary expertises provide a broad-based, yet focused, approach to addressing fundamental questions about the role of activated glia and glial-neuronal interactions in neurodegeneration.